WO2019233883A1 - Tetrahydrobenzofuro[2,3-c]pyridine and beta-carboline compounds for the treatment, alleviation or prevention of disorders associated with tau aggregates - Google Patents

Tetrahydrobenzofuro[2,3-c]pyridine and beta-carboline compounds for the treatment, alleviation or prevention of disorders associated with tau aggregates Download PDF

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WO2019233883A1
WO2019233883A1 PCT/EP2019/064144 EP2019064144W WO2019233883A1 WO 2019233883 A1 WO2019233883 A1 WO 2019233883A1 EP 2019064144 W EP2019064144 W EP 2019064144W WO 2019233883 A1 WO2019233883 A1 WO 2019233883A1
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compound
mmol
reaction mixture
tau
group
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PCT/EP2019/064144
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English (en)
French (fr)
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Sreenivasachary NAMPALLY
Emanuele Gabellieri
Jerome Molette
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Ac Immune Sa
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Priority to MX2020013115A priority Critical patent/MX2020013115A/es
Application filed by Ac Immune Sa filed Critical Ac Immune Sa
Priority to JP2020566895A priority patent/JP7357371B2/ja
Priority to AU2019280590A priority patent/AU2019280590B2/en
Priority to BR112020022245-3A priority patent/BR112020022245A2/pt
Priority to CN201980037185.4A priority patent/CN112351984B/zh
Priority to US17/053,459 priority patent/US11684625B2/en
Priority to KR1020207034883A priority patent/KR102550423B1/ko
Priority to EA202092557A priority patent/EA202092557A1/ru
Priority to EP19730702.8A priority patent/EP3802533A1/en
Priority to CA3102343A priority patent/CA3102343C/en
Publication of WO2019233883A1 publication Critical patent/WO2019233883A1/en
Priority to IL279106A priority patent/IL279106A/en
Priority to US18/295,667 priority patent/US20230255976A1/en

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
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    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention relates to novel compounds that can be employed in the treatment, alleviation or prevention of a group of disorders and abnormalities associated with Tau (Tubulin associated unit) protein aggregates including, but not limited to, Neurofibrillary Tangles (NFTs), such as Alzheimer’s disease (AD).
  • Tau Tubulin associated unit
  • NFTs Neurofibrillary Tangles
  • AD Alzheimer’s disease
  • amyloid beta amyloid beta
  • ADanPP ADan protein PP
  • Tau alpha-synuclein
  • TDP-43 TAR DNA-binding protein 43
  • htt huntingtin
  • Amyloid or amyloid-like deposits result from misfolding of proteins followed by aggregation to give b-sheet assemblies in which multiple peptides or proteins are held together by inter-molecular hydrogen-bonds. While amyloid or amyloid-like proteins have different primary amino acid sequences, their deposits often contain many shared molecular constituents, in particular the presence of b-sheet quaternary structures. The association between amyloid deposits and diseases remains largely unclear. A diverse range of protein aggregates, including both those associated and not associated with disease pathologies, have been found to be toxic suggesting that the common molecular features of amyloid are implicated or responsible for disease on-set (Bucciantini et al., Nature, 2002, 416, 507-1 1 ).
  • AD Alzheimer’s disease
  • amyloid-beta amyloid-beta
  • the other major neuropathological hallmarks in AD are the intracellular neurofibrillary tangles (NFT) that originate by the aggregation of the hyperphosphorylated Tau protein, misfolded Tau or pathological Tau and its conformers.
  • NFT neurofibrillary tangles
  • AD shares its etiopathology with many neurodegenerative tauopathies, in particular with specified types of frontotemporal dementia (FTD).
  • FTD frontotemporal dementia
  • the Tau protein is a freely soluble, "naturally unfolded” protein that binds avidly to microtubuli (MT) to promote their assembly and stability.
  • MT are of major importance for the cytoskeletal integrity of neurons - and thereby for the proper formation and functioning of neuronal circuits, hence for learning and memory.
  • the binding of Tau to MT is controlled by dynamic phosphorylation and de-phosphorylation, as demonstrated mainly in vitro and in non-neuronal cells.
  • Tau pathology (tauopathy) develops later than amyloid pathology, but it is still discussed controversially if Ab protein is the causative agent in AD which constitutes the essence of the so-called amyloid cascade hypothesis (Hardy et al., Science 1992, 256, 184-185; Musiek et al., Nature Neurosciences 2015, 18(6), 800-806).
  • tauopathies include, but are not limited to, Alzheimer’s disease (AD), familial AD, PART (primary age-related Tauopathy), Creutzfeldt-Jacob disease, dementia pugilistica, Down’s Syndrome, Gerstmann-Straussler- Scheinker disease (GSS), inclusion-body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Parkinsonism-dementia complex of Guam, non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain disease, corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Hallervorden- Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallido-ponto
  • WO2011/128455 refers to specific compounds which are suitable for treating disorders associated with amyloid proteins or amyloid-like proteins.
  • Figure 1 Reduction of intracellular Tau misfolding by immunocytochrmistry in differentiated neuroblastoma cells with Example 44. Data are shown as mean + SD.
  • NFTs such as Alzheimer’s disease
  • the present inventors have surprisingly found that these objects can be achieved by the compounds of formula (I) as described hereinafter.
  • the compounds of formula (I) display a high capability in decreasing Tau aggregates by, recognizing aggregated Tau and disaggregating Tau, for example by changing the Tau aggregate molecular conformation.
  • Some compounds of formula (I) prevent the formation of Tau aggregates, and/or interfere intracellularly with Tau aggregates. While not wishing to be bound by theory, it is assumed that the compounds of formula (I) inhibit the Tau aggregation or disaggregate preformed Tau aggregates including when present intracellularly. Due to their unique design features, these compounds display properties such as appropriate lipophilicity and molecular weight, brain uptake and pharmacokinetics, cell permeability, solubility and metabolic stability, in order to be a successful medicament for the treatment, alleviation or prevention of tauopathies.
  • Tau is able to both propagate from cell-to-cell and that certain forms of Tau (acting as seeds) are able to induce the structural change of native Tau protein within the healthy cell to undergo misfolding and aggregation. It is considered that aggregated Tau is responsible for the seeding and thus of the Tau pathology spreading.
  • the compounds of this invention can interfere intracellularly with aggregated Tau and can therefore be expected to reduce Tau pathology spreading and finally prevent or reduce the associated cognitive deficits in AD.
  • the present invention discloses novel compounds of formula (I) having capabilities to decrease Tau aggregates, recognize aggregated Tau and disaggregate Tau, for example by changing the Tau aggregate molecular conformation.
  • the present invention discloses some novel compounds of formula (I) having capabilities to prevent the formation of Tau aggregates, and/or to interfere intracellularly with Tau aggregates.
  • the present invention provides methods for the treatment of disorders and abnormalities associated with Tau protein aggregates including, but not limited to, NFTs, using a compound of formula (I) or a pharmaceutical composition thereof.
  • the present invention further provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier or excipient.
  • A is selected from the group consisting of
  • B is selected from the group consisting of O and NR a ;
  • E and V are independently selected from the group consisting of N, NR 5 , O and S;
  • G is selected from the group consisting of a benzene ring and a pyridine ring;
  • J is selected from the group consisting of O, N-R 1 and CH 2 or J is selected from the group consisting of CH or C if J is attached to R 2 ;
  • Y, Y 1 , Y 2 and Y 3 are CZ;
  • Z is independently selected from the group consisting of H, halogen, O-alkyl, alkyl and CN;
  • R is independently selected from the group consisting of
  • R a is selected from the group consisting of H and alkyl
  • R d , R e , R f , and R 9 are independently selected from the group consisting of H and alkyl, or any two of R d , R e , R f , and R 9 may be joined to form a 3 to 8-membered ring;
  • R j is independently selected from the group consisting of -halogen, -O-alkyl, -NR 3 R 4 , -
  • a C1 -2 carbon atom- containing bridge or a bond can be present between the a carbon atom and the c or d carbon atom or wherein a C1 -2 carbon atom-containing bridge or a bond can be present between the b carbon atom and the c or d carbon atom;
  • R 1 is selected from the group consisting of H and alkyl
  • R 2 is independently selected from the group consisting of alkyl, or -O-alkyl and wherein if two R 2 are geminal they can be joined to form a 3 to 6-membered ring;
  • R 3 and R 4 are independently selected from the group consisting of H and alkyl;
  • R 5 is selected from the group consisting of H and alkyl;
  • n is 0, 1 , 2, 3 or 4;
  • r and s are independently 0, 1 , 2 or 3;
  • t and u are independently 1 , 2 or 3.
  • R a , R j and Z are as defined in item 1 and p is 1 or 2.
  • p is 1 or 2.
  • a pharmaceutical composition comprising a compound as defined in any one of items 1 to 5 and optionally a pharmaceutically acceptable carrier or excipient.
  • a method of treating, preventing or alleviating a disorder associated with Tau protein aggregates comprising administering an effective amount of a compound as defined in any one of items 1 to 5 to a subject in need thereof.
  • a method of decreasing tau aggregation comprising administering an effective amount of a compound as defined in any one of items 1 to 5 to a subject in need thereof.
  • a method of preventing the formation of Tau aggregates and/or of inhibiting Tau aggregation comprising administering an effective amount of a compound as defined in any one of items 1 to 5 to a subject in need thereof.
  • a method of interfering intracellularly with Tau aggregates comprising administering an effective amount of a compound as defined in any one of items 1 to 5 to a subject in need thereof.
  • a mixture comprising a compound as defined in any one of items 1 to 5 and at least one further biologically active compound selected from a therapeutic agent different from the compound as defined in any one of items 1 to 5, a pharmaceutically acceptable carrier, a diluent and an excipient.
  • the mixture according to item 20, wherein the further biologically active compound is a compound used in the treatment of amyloidosis.
  • the further biologically active compound is selected from the group consisting of compounds against oxidative stress, anti-apoptotic compounds, metal chelators, inhibitors of DNA repair such as pirenzepine and metabolites, 3-amino-1-propanesulfonic acid (3APS), 1 ,3-propanedisulfonate (1 ,3PDS), a-secretase activators, b- and g-secretase inhibitors, Tau proteins, neurotransmitter, b-sheet breakers, attractants for amyloid beta clearing / depleting cellular components, inhibitors of N-terminal truncated amyloid beta including pyroglutamated amyloid beta 3-42, anti-inflammatory molecules, or cholinesterase inhibitors (ChEls) such as tacrine, rivastigmine, donepezil, and/or galantamine, M1 agonists, other drugs including any amyloid or Tau modifying drug and nutritive supplements, an antibody
  • the mixture according to item 22, wherein the further biologically active compound is a cholinesterase inhibitor (ChEI).
  • the mixture according to item 22, wherein the further biologically active compound is selected from the group consisting of tacrine, rivastigmine, donepezil, galantamine, niacin and memantine.
  • the mixture according to item 22, wherein the further biologically active compound is an antibody, particularly a monoclonal antibody, including any functionally equivalent antibody or functional parts thereof.
  • Alkyl refers to a saturated straight or branched organic moiety consisting of carbon and hydrogen atoms.
  • suitable alkyl groups have 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and isobutyl.
  • Hal or "halogen” refers to F, Cl, Br, and I, preferably F.
  • 3- to 8-membered ring refers to a three-, four-, five-, six-, seven- or eight-membered ring wherein none, one or more of the carbon atoms in the ring have been replaced by 1 or 2 (for the three- membered ring), 1 , 2 or 3 (for the four-membered ring), 1 , 2, 3, or 4 (for the five-membered ring) or 1 , 2, 3, 4, or 5 (for the six-membered ring) 1 , 2, 3, 4, 5 or 6 (for the seven-membered ring), or 1 , 2, 3, 4, 5, 6 or 7 (for the eight-membered ring) of the same or different heteroatoms, whereby the heteroatoms are selected from O, N and S.
  • Compounds of the present invention having one or more optically active carbons can exist as racemates and racemic mixtures (including mixtures in all ratios), stereoisomers (including diastereomeric mixtures and individual diastereomers, enantiomeric mixtures and single enantiomers, mixtures of conformers and single conformers), tautomers, atropisomers, and rotamers. All isomeric forms are included in the present invention.
  • Compounds described in this invention containing olefinic double bonds include E and Z geometric isomers. Also included in this invention are all pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates and solvates.
  • polymorphs refers to the various crystalline structures of the compounds of the present invention. This may include, but is not limited to, crystal morphologies (and amorphous materials) and all crystal lattice forms. Salts of the present invention can be crystalline and may exist as more than one polymorph.
  • Solvates, hydrates as well as anhydrous forms of the salt are also encompassed by the invention.
  • the solvent included in the solvates is not particularly limited and can be any pharmaceutically acceptable solvent. Examples include water and Ci_4 alcohols (such as methanol or ethanol).
  • "Pharmaceutically acceptable salts" are defined as derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid and the like; and the salts prepared from organic acids such as, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic acid, and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
  • Organic solvents include, but are not limited to, nonaqueous media like ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts can be found in Remington’s Pharmaceutical Sciences, 18 th ed. , Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is hereby incorporated by reference.
  • the compounds of the present invention can also be provided in the form of a prodrug, namely a compound which is metabolized in vivo to the active metabolite.
  • a prodrug means any covalently bonded compound which releases the active parent pharmaceutical due to in vivo biotransformation.
  • “Pharmaceutically acceptable” is defined as those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
  • the patients or subjects in the present invention are typically animals, particularly mammals, more particularly humans.
  • Tau refers to a highly soluble microtubule binding protein mostly found in neurons and includes the major 6 isoforms, cleaved or truncated forms, and other modified forms such as arising from phosphorylation, glycosylation, glycation, prolyl isomerization, nitration, acetylation, polyamination, ubiquitination, sumoylation and oxidation.
  • Aggregated Tau refers to aggregated monomers of Tau peptides or proteins which are folded into the oligomeric or polymeric structures.
  • NFTs Neuroofibrillary Tangles
  • the present invention relates to a compound of formula (I):
  • A is selected from the group consisting of
  • G is selected from a benzene ring and a
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is selected from
  • A is selected from
  • A is In the above definitions of A and the preferred embodiments thereof,
  • A is substituted by one or more substituents R j , for instance, R j can be present one or two times. If A is phenyl ring, then 1 or 2 substituents can be preferably present. If A is a pyridine ring, then 1 substituent can be preferably present.
  • R j can be present one or two times. If A is phenyl ring, then 1 or 2 substituents can be preferably present. If A is a pyridine ring, then 1 substituent can be preferably present.
  • B is selected from the group consisting of O and NR a . More preferably B is NR a .
  • E and V are independently selected from the group consisting of N, NR 5 , O and S, so that
  • J is selected from the group consisting of O, N-R 1 and CH 2 or J is selected from the group consisting of CH or C if J is attached to R 2 .
  • J is O
  • J is N-R 1 (preferably N-Me) and in a further embodiment J is CH 2 , CH or C.
  • Y, Y 1 , Y 2 and Y 3 are CZ, more preferably Y, Y 1 , Y 2 and Y 3 are CH.
  • Z is independently selected from the group consisting of H, halogen (preferably F), O-alkyl, alkyl and CN, preferably H, halogen (preferably F), and O-alkyl.
  • one Z is halogen (preferably F), or O-alkyl and the other Z are H.
  • one Z is halogen (preferably F) and the other Z are H.
  • R is independently selected from the group consisting preferably R
  • R a is selected from the group consisting of H and alkyl, more preferably H and Me.
  • R d , R e , R f , and R g are independently selected from the group consisting of H and alkyl, or any two of R d , R e , R f , and R g may be joined to form a 3 to 8-membered ring.
  • R d , R e , R f , R g are independently H or R d and R f can be joined together to form a C1 -2 carbon atom-containing bridge. More preferably R d , R e , R f , and R g are H.
  • R j is independently selected from the group consisting of -halogen, -O-alkyl, -NR 3 R 4 , -CN,
  • R j is selected from the group consisting of -halogen
  • R 1 is selected from the group consisting of H and alkyl, preferably alkyl, more preferably CH3.
  • R 2 is independently selected from the group consisting of alkyl, or -O-alkyl and wherein if two R 2 are geminal they can be joined to form a 3 to 6-membered ring.
  • R 2 is alkyl, in another embodiment R 2 is -O-alkyl, in a further embodiment two R 2 that are geminal can be joined to form a 3 to 6-membered ring.
  • R 3 and R 4 are independently selected from the group consisting of H and alkyl. In one embodiment R 3 or R 4 is alkyl and the other is H. In another embodiment R 3 is alkyl and R 4 is alkyl. In a further embodiment R 3 and R 4 are H.
  • R 5 is selected from the group consisting of H and alkyl. In one embodiment R 5 is H. In another embodiment R 5 is alkyl. n is 0, 1 , 2, 3 or 4, more preferably 0, 1 or 2, even more preferably n is 0. p is 1 or 2, more preferably 1. r and s are independently 0, 1 , 2 or 3. t and u are independently 1 , 2 or 3.
  • the invention also provides a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula (I) optionally in admixture with a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.
  • compositions are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, 15 th Ed., Mack Publishing Co., New Jersey (1975).
  • the pharmaceutical excipient can be selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the excipient must be acceptable in the sense of being not deleterious to the recipient thereof.
  • compositions of the present invention may comprise, for example, carriers, vehicles, diluents, solvents such as monohydric alcohols such as ethanol, isopropanol and polyhydric alcohols such as glycols and edible oils such as soybean oil, coconut oil, olive oil, safflower oil cottonseed oil, oily esters such as ethyl oleate, isopropyl myristate, binders, adjuvants, solubilizers, thickening agents, stabilizers, disintegrants, glidants, lubricating agents, buffering agents, emulsifiers, wetting agents, suspending agents, sweetening agents, colorants, flavors, coating agents, preservatives, antioxidants, processing agents, drug delivery modifiers and enhancers such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxy
  • the routes for administration (delivery) of the compounds of the invention include, but are not limited to, one or more of: oral (e. g. as a tablet, capsule, or as an ingestible solution), topical, mucosal (e. g. as a nasal spray or aerosol for inhalation), nasal, parenteral (e. g. by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, epidural and sublingual.
  • oral e. g. as a tablet, capsule, or as an ingestible solution
  • mucosal e. g. as a nasal spray or aerosol for inhalation
  • nasal parenteral (e. g. by an injectable form)
  • the compounds can be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
  • the tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine
  • disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glyco
  • Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
  • the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • the compounds of the present invention are administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously administering the compounds; and/or by using infusion techniques.
  • parenteral administration the compounds are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • the compounds of the present invention can be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurized container, pump, spray or nebulizer with the use of a suitable propellant, e. g.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e. g.
  • Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds of the present invention can be administered in the form of a suppository or pessary, or it may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
  • the compounds of the present invention may also be dermally or transdermally administered, for example, by the use of a skin patch.
  • the compounds may also be administered by the pulmonary or rectal routes. They may also be administered by the ocular route.
  • the compounds can be formulated as micronized suspensions in isotonic, pH was adjusted, sterile saline, or, preferably, as solutions in isotonic, pH was adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.
  • the compounds of the present invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water.
  • they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • a physician will determine the actual dosage which will be most suitable for an individual subject.
  • the specific dose level and frequency of dosage for any particular individual may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.
  • a proposed dose of the compounds according to the present invention for administration to a human is 0.1 mg to 1 g, preferably 1 mg to 500 mg of the active ingredient per unit dose.
  • the unit dose may be administered, for example, 1 to 4 times per day.
  • the dose will depend on the route of administration. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient as well as the severity of the condition to be treated. The precise dose and route of administration will ultimately be at the discretion of the attendant physician or veterinarian.
  • the compounds of the invention may also be used in combination with other therapeutic agents.
  • the dose of each compound may differ from that when the compound is used alone.
  • the combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.
  • administration either the compound of the invention or the second therapeutic agent may be administered first.
  • administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.
  • the two compounds When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation.
  • they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
  • the pharmaceutical compositions of the invention can be produced in a manner known per se to the skilled person as described, for example, in Remington's Pharmaceutical Sciences, 15 th Ed., Mack Publishing Co., New Jersey (1975).
  • the diseases or conditions that can be treated, alleviated or prevented with the compounds of the present invention are disorders or abnormalities associated with Tau protein aggregates such as neurodegenerative disorders. Examples of diseases and conditions which can be treated, alleviated or prevented are caused by or associated with the formation of neurofibrillary lesions. This is the predominant brain pathology in tauopathy.
  • the diseases and conditions comprise a heterogeneous group of neurodegenerative diseases or conditions including diseases or conditions which show co-existence of Tau and amyloid pathologies.
  • AD Alzheimer’s disease
  • familial AD familial AD
  • PART Primary Age-Related Tauopathy
  • Creutzfeldt-Jacob disease dementia pugilistica, Down’s Syndrome
  • Gerstmann- Straussler-Scheinker disease GSS
  • inclusion-body myositis prion protein cerebral amyloid angiopathy
  • traumatic brain injury TBI
  • amyotrophic lateral sclerosis ALS
  • Parkinsonism- dementia complex of Guam non-Guamanian motor neuron disease with neurofibrillary tangles
  • argyrophilic grain disease corticobasal degeneration (CBD)
  • Hallervorden-Spatz disease multiple system atrophy
  • the diseases and conditions which can be treated, alleviated or prevented include Alzheimer’s disease (AD), as well as other neurodegenerative tauopathies such as Creutzfeldt-Jacob disease, dementia pugilistica, amyotrophic lateral sclerosis (ALS), argyrophilic grain disease, corticobasal degeneration (CBD), frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Pick’s disease (PiD), progressive supranuclear palsy (PSP), tangle predominant dementia, Parkinson dementia complex of Guam, Hallervorden-Spatz disease, chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), and other frontotemporal lobar degeneration. More preferably Alzheimer’s disease (AD), corticobasal degeneration (CBD), Pick’s disease (PiD), and progressive supranuclear palsy (PSP).
  • AD Alzheimer’s disease
  • CBD corticobasal degeneration
  • PiD progressive supranuclear
  • the compounds of the present invention can also be employed to decrease protein aggregation, in particular Tau aggregation.
  • the ability of a compound to decrease of Tau aggregation can, for example, be determined using the ThT assay (Hudson et al., FEBS J., 2009, 5960-72).
  • the compounds of the invention can be used in the treatment of a wide range of disorders in which the neuroinflammation process is associated with misfolding and/or pathologic aggregation of Tau protein.
  • the compounds of the present invention can be used as an analytical reference or an in vitro screening tool for characterization of tissue with Tau pathology and for testing of compounds targeting Tau pathology on such tissue.
  • the compounds according to the present invention can also be provided in the form of a mixture with at least one further biologically active compound and/or a pharmaceutically acceptable carrier and/or a diluent and/or an excipient.
  • the compound and/or the further biologically active compound are preferably present in a therapeutically effective amount.
  • the nature of the further biologically active compound will depend on the intended use of the mixture.
  • the further biologically active substance or compound may exert its biological effect by the same or a similar mechanism as the compound according to the invention or by an unrelated mechanism of action or by a multiplicity of related and/or unrelated mechanisms of action.
  • the further biologically active compound may include neutron-transmission enhancers, psychotherapeutic drugs, acetylcholineesterase inhibitors, calcium-channel blockers, biogenic amines, benzodiazepine tranquillizers, acetylcholine synthesis, storage or release enhancers, acetylcholine postsynaptic receptor agonists, monoamine oxidase-A or -B inhibitors, N-methyl-D- aspartate glutamate receptor antagonists, non-steroidal anti-inflammatory drugs, antioxidants, and serotonergic receptor antagonists.
  • neutron-transmission enhancers may include neutron-transmission enhancers, psychotherapeutic drugs, acetylcholineesterase inhibitors, calcium-channel blockers, biogenic amines, benzodiazepine tranquillizers, acetylcholine synthesis, storage or release enhancers, acetylcholine postsynaptic receptor agonists, monoamine oxidase-A or -B inhibitors, N
  • the further biologically active compound can be selected from the group consisting of a compound used in the treatment of amyloidosis, compounds against oxidative stress, anti-apoptotic compounds, metal chelators, inhibitors of DNA repair such as pirenzepine and metabolites, 3-amino-1-propanesulfonic acid (3APS), 1 ,3- propanedisulfonate (1 ,3PDS), a-secretase activators, b- and g-secretase inhibitors, Tau proteins, neurotransmitter, b-sheet breakers, attractants for amyloid beta clearing / depleting cellular components, inhibitors of N-terminal truncated amyloid beta including pyroglutamated amyloid beta 3-42, anti-inflammatory molecules, or cholinesterase inhibitors (ChEls) such as tacrine, rivastigmine, donepezil, and/or galantamine, M1 agonists, other drugs including any amyloid or Tau modifying drug and nutrient
  • the mixtures according to the invention may comprise niacin or memantine together with a compound according to the present invention and, optionally, a pharmaceutically acceptable carrier and/or a diluent and/or an excipient.
  • mixtures comprise as a further biologically active compound “atypical antipsychotics” such as, for example clozapine, ziprasidone, risperidone, aripiprazole or olanzapine for the treatment of positive and negative psychotic symptoms including hallucinations, delusions, thought disorders (manifested by marked incoherence, derailment, tangentiality), and playful or disorganized behavior, as well as anhedonia, flattened affect, apathy, and social withdrawal, together with a compound according to the invention and, optionally, a pharmaceutically acceptable carrier and/or a diluent and/or an excipient.
  • “atypical antipsychotics” such as, for example clozapine, ziprasidone, risperidone, aripiprazole or olanzapine for the treatment of positive and negative psychotic symptoms including hallucinations, delusions, thought disorders (manifested by marked incoherence, derailment, tangentiality
  • the invention also includes all suitable isotopic variations of the compounds of the invention.
  • An isotopic variation of the compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 0, 35 S, 18 F and 36 CI respectively.
  • Certain isotopic variations of the invention for example, those in which a radioactive isotope such as 3 H or 14 C is incorporated, are useful in drug and/or substrate tissue distribution studies.
  • Tritiated, i.e. , 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and delectability.
  • 18 F-labeled compounds are particularly suitable for imaging applications such as PET.
  • substitution with isotopes such as deuterium, i.e., 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples and Preparations hereafter using appropriate isotopic variations of suitable reagents.
  • the compounds of the present invention can be synthesized by one of the general methods shown in the following schemes. These methods are only given for illustrative purposes and should not to be construed as limiting.
  • the NH-moiety of the tricyclic building blocks was treated with either methyl iodide or tosyl chloride in an appropriate solvent using a suitable base to afford the N-methyl or N-tosyl derivatives after purification.
  • the Boc-protecting group was cleaved by acid treatment in an appropriate solvent to afford the desired N-methyl or N-tosyl tricyclic building blocks after purification. In case there was no base treatment after cleavage of the Boc-protecting group, the corresponding salts were obtained.
  • the NH- moiety of the indole moiety was then treated with tosyl chloride in an appropriate solvent using a suitable base to afford the N-tosyl derivatives after purification.
  • the Boc-protecting group was cleaved by acid treatment in an appropriate solvent to afford the tricyclic building blocks containing a secondary amine after purification. In case there was no base treatment after cleavage of the Boc-protecting group, the corresponding salts were obtained.
  • the leaving group X was replaced via nucleophilic substitution by the primary or secondary amines to afford the corresponding amino- substituted benzo[cf]thiazole or benzo[cf]oxazole derivatives after purification.
  • the desired benzo[cf]thiazole or benzo[d]oxazole derivatives were obtained by performing the nucleophilic substitution reaction under microwave conditions.
  • the tricyclic building blocks containing a N-tosyl group at the indole moiety were coupled with substituted benzo[cf]thiazole or benzo[cf]oxazole derivatives, or substituted phenyl or pyridine derivatives, via palladium chemistry with a suitable palladium source like Palladium(ll) acetate (Pd(OAc)2), Tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba)3) a suitable ligand like 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene (Xantphos), 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) and a suitable base like Cesium carbonate (CS2CO3) and
  • the tosyl protected compounds were generally treated with a suitable base like Sodium ferf-butoxide (NaOtBu) in appropriate solvents mixture like Dioxane and Methanol to afford the desired compounds of formula (I) after purification.
  • a suitable base like Sodium ferf-butoxide (NaOtBu) in appropriate solvents mixture like Dioxane and Methanol to afford the desired compounds of formula (I) after purification.
  • R x Hal Pd-cat, ligand base, solvent morpholine
  • the tricyclic building blocks containing a N-tosyl- or NCH 3 -group at the indole moiety were coupled with halogen-substituted benzo[cf]thiazole or benzo[cf]oxazole derivatives via palladium chemistry with a suitable palladium source like Palladium(ll) acetate (Pd(OAc)2), Tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba) 3 ) a suitable ligand like 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene (Xantphos), 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) and a suitable base like Cesium carbonate (Cs 2 C
  • GC-MS data were collected using an Agilent 7890B gas chromatograph and 5977B mass spectrometer. Infrared spectra were obtained on a PerkinElmer spectrometer. Chromatography was performed using silica gel (Fluka: Silica ge10l 60, 0.063-0.2 mm) and suitable solvents as indicated in specific examples. Flash purification was conducted with a Biotage Isolera with HP-Sil or KP-NH SNAP cartridges (Biotage) and the solvent gradient indicated in specific examples. Thin layer chromatography (TLC) was carried out on silica gel plates with UV detection.
  • TLC Thin layer chromatography
  • the minor regioisomer was isolated as well (0.3 g, 4.3 %).
  • reaction mixture was stirred at room temperature for 12 h. After the completion of the reaction, the reaction mixture was evaporated to remove the solvent and washed with diethyl ether to afford the title compound as an off-white solid (0.75 g 96 %).
  • the crude material was basified by using 30% sodium hydroxide solution, followed by extraction using ethyl acetate (50 mL). The ethyl acetate layer was washed with water (20 mL) and brine solution (10 mL). The organic layer was dried over Na 2 S0 4 , filtered and evaporated to afford the crude title compound as a pale brown gummy mass (1.6 g, 83 %). The crude product was taken as such for next step.
  • the reaction mixture was cooled to 0° C and quenched with ice water, followed by extraction using ethyl acetate (50 mL). The ethyl acetate layer was washed with water (10 mL) and brine solution (10 mL). The organic layer was dried over Na2S0 4 , filtered and evaporated to afford the crude product, which was purified by silica gel column using 15% to 25% of ethyl acetate in petrol ether to afford the title compound as an off-white solid (0.9 g, 61 %).
  • the reaction mixture was cooled to 0° C and quenched with ice water (500 mL), followed by extraction using ethyl acetate (3 x 500 mL).
  • the combined organic extracts were washed with water (2 x 500 mL), brine (1 x 250 mL) and dried over Na 2 S0 4 , filtered and evaporated under reduced pressure to afford the crude product which was triturated with hexane (250 mL).
  • the solid thus obtained was filtered, washed with hexane (2 x 100 mL) and dried to afford the title compound as pale brown solid (130 g, 83%).
  • the reaction mixture was cooled to 0° C and quenched with ice water (500 mL), followed by extraction using ethyl acetate (3 x 500 mL).
  • the combined organic extracts were washed with water (2 x 300 mL), brine (1 x 250 mL) and dried over Na 2 S0 4 , filtered and evaporated under reduced pressure to afford the crude product which was triturated with hexane (250 mL).
  • the solid thus obtained was filtered, washed with hexane (2 x100 mL) and dried to afford the title compound as brown solid (93 g, 88%).
  • reaction mixture was filtered through celite pad, and washed with ethyl acetate to yield the crude product.
  • the crude material was purified by silica-gel (60-120) column chromatography using dichloromethane/methanol (99:1 ) to afford the title compound as a brown solid (1 g, 25%).
  • Step C To a suspension of the title compound from Step B above (0.50 g, 2.24 mmol) in acetonitrile (10 mL) at 0 °C, was added ferf-butyl nitrite (0.4 mL, 3.35 mmol) over a period of 10 min with a syringe. Then, copper (II) bromide (0.6g, 2.68 mmol) was added portion wise at 0°C and stirred for 30 min. The reaction mixture was allowed to warm to 25 °C for 1 h and heated to 60 °C for 4 h.
  • reaction mixture was filtered through celite pad, and washed with ethyl acetate to yield the crude product.
  • the crude material was purified by silica-gel (60-120) column chromatography using dichloromethane/methanol (99:1 ) to afford the title compound as a pale brown solid (0.27 g, 42%).
  • Step A Step B Step c morpholine, Et 3 N m CH 2 CI 2
  • the dichloromethane layer was concentrated under reduced pressure to afford the title compound (10.0 g, Crude) as a brown oil.
  • the dichloromethane layer was concentrated under reduced pressure to afford the title compound (10.0 g, Crude) as a brown oil.
  • Step A To a solution of commercially available 5-bromo-2-fluoropyridine (0.3 g, 1.70 mmol) and 6-oxa-3- azabicyclo[3.1.1]heptane 4-methylbenzenesulfonate (0.463 g, 1.7 mmol) in DMF potassium carbonate was added (0.707 g, 5.1 1 mmol). The reaction heated to 90° C for 12 h.
  • the reaction mixture was diluted with ethyl acetate (30 mL) and water (30 mL).
  • the organic phase was separated and the aqueous phase was extracted with ethyl acetate two more times.
  • the combined organic phase was dried over Na2S0 4 , filtered and the solvents were evaporated under reduced pressure.
  • Step A To a solution of commercially available 3,6-dichloropyridazine (0.500g, 3.36mmol) and (2R)-2- methylmorpholine (0.339g,3.36mmol) in ethanol (15 mL) was added triethylamine (0.509g, 5.03mmol) and the reaction was heated to 80° C for 12 h. The reaction mixture was concentrated under reduced pressure. The crude purified on HP-Sil column (Biotage), by employing a Petroleum ether/ethyl acetate gradient (100/0 -> 70/30) to afford title compound (0.250 g, 34.5%).
  • Example 44 To a solution of Example 44 in THF (15. OmL), sodium hydride (60%) (0.0412g,1.79mmol) was added slowly at 0°C then stirred it for 1 hr at 25°C. Ethyl Iodide (0.305g,0.00179mol) in 15. OmL THF was added slowly at 0°C then stirred it for 2hr at 25°C. The reaction mixture was monitored by LCMS, the reaction mixture was diluted with water (50. OmL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate two more time . The combined organic phase was dried over Na2S0 4 , filtered and the solvents were evaporated under reduced pressure. The crude purified on HP-Sil column (biotage) by employing a Ethyl Acetate/ Petrol uem Ether (50/50) gradient to afford title compound as an off white solid.
  • the longest isoform of human Tau (2N4R; 441 amino acids) was expressed in bacteria and purified.
  • 35 pM of recombinant full-length (fl)Tau in PBS were aggregated for 24 hours at 37°C in presence of 50 pM of heparin (Sigma-Aldrich) and 10 mM of DTT (Sigma-Aldrich) under shaking at 750 RPM.
  • Compounds were dissolved in anhydrous dimethyl sulfoxide (DMSO, Sigma-Aldrich) to reach a concentration of 10 mM.
  • DMSO dimethyl sulfoxide
  • fITau aggregates and serial dilutions of compounds were mixed together in PBS (volume 50 pL) to a final concentration of 2 pM of fITau aggregates and from 160 to 0.04 pM of compounds.
  • the mixture was incubated for 30 minutes at room temperature (RT), then 40 pL of this mixture were transferred into a black 384-well plate assay (Perkin-Elmer) and mixed with 10 pL of 100 pM ThT in 250 mM glycine (both from Sigma-Aldrich) in PBS.
  • Fluorescence quantitative fluorescence units; RFU
  • RFU relative fluorescence units
  • Percentage of fITau disaggregation was then calculated and the half maximal effective concentration (ECso) was determined using GraphPad Prism version 5 (GraphPad Software) assuming a one-binding site fitting model.
  • the Tau K18 fragment encompassing amino acids 244 to 372 of the longest isoform (2N4R) of human Tau441 , was expressed in bacteria and purified or bought from SignalChem.
  • Compounds were dissolved in anhydrous dimethyl sulfoxide (DMSO, Sigma-Aldrich) to reach a concentration of 10 mM.
  • DMSO dimethyl sulfoxide
  • K18 aggregates and serial dilutions of compounds were mixed together in PBS (volume 50 pL) to a final concentration of 2 pM of K18 aggregates and from 160 to 0.04 pM of compounds.
  • the mixture was incubated for 30 minutes at room temperature (RT), then 40 pL of this mixture were transferred into a black 384-well plate assay (Perkin-Elmer) and mixed with 10 pL of 100 pM ThT in 250 mM glycine (both from Sigma- Aldrich) in PBS.
  • Fluorescence (relative fluorescence units; RFU) was measured in monoplicate or duplicate on a Tecan reader (excitation: 440 nm; emission: 485 nm).
  • Percentage of K18 disaggregation was then calculated and half maximal effective concentration (EC50) was determined using GraphPad Prism version 5 (GraphPad Software) assuming a one-binding site fitting model. The following example compounds were measured:
  • a human neuroblastoma cell line overexpressing the full-length form of human Tau carrying the P301 L mutation was cultured in complete medium [DMEM-F12 4.5 g/L Glutamax (Invitrogen), 15% FBS (Biochrom), 1 % Peni/Strep (Invitrogen) supplemented with 2.5 pg/ml of G418 (Sigma- Aldrich) selection antibiotic].
  • DMEM-F12 4.5 g/L Glutamax (Invitrogen), 15% FBS (Biochrom), 1 % Peni/Strep (Invitrogen) supplemented with 2.5 pg/ml of G418 (Sigma- Aldrich) selection antibiotic.
  • the day before the experiment 5x10 5 cells/well were plated in a 6 well plate in 3 mL of complete medium. The next day, cells were incubated with DMSO or a compound of the present invention at 5 pM for additional 24 h at 37°C.
  • Phosphorylated, aggregated, and total Tau were quantified by AlphaLisa using the following antibody pairs:
  • the Tau13 (Abeam) was biotinylated using EZ-Link® NHS-PEO Solid Phase biotinylation kit (Thermo Scientific), while the HT7-biotin was from a commercial source (Thermo Scientific).
  • a human neuroblastoma cell line overexpressing the full-length form of human Tau carrying the P301 L mutation were cultured in complete medium [DMEM-F12 4.5 g/L Glutamax (Invitrogen), 15% FBS (Biochrom), 1 % Peni/Strep (Invitrogen) supplemented with 2.5 pg/ml of G418 (Sigma-
  • RA retinoic acid
  • compounds were dispensed on the cells at concentrations between of 0.1 and 10 nM for 24 hours. After the incubation with the compounds cells were fixed in 4% PFA for 15 min and washed 3 times in PBS. Then cells were blocked in 10% neat goat serum (NGS), 0.25% Triton X-100 in PBS for 2h at room temperature. Permeabilized fixed cells were then incubated overnight in 5% NGS/0.25% Triton X-100 in PBS with monoclonal anti-mouse MC1 antibody (provided by Prof.
  • the isoform of human Tau (2N4R; 441 amino acids) was purchased from Biotechne (USA). The protein was expressed in bacteria E coli, purified and concentrated in PBS to a final concentration of 50 mM.
  • homogenization buffer 0.5 M NaCI in RAB buffer (100 mM 2-(N-morpholino) ethanesulfonic acid (MES), 1 mM EGTA, 0.5 mM MgS04, 2 mM DTT, pH 6.8) supplemented with protease inhibitors (Complete; Roche 1 1697498001 )] in a glass Dounce homogenizer.
  • MES 2-(N-morpholino) ethanesulfonic acid
  • protease inhibitors Complete; Roche 1 1697498001
  • the homogenate was then incubated at 4°C for 20 min to let depolymerize any residual microtubules, before being transferred into polycarbonate centrifuge bottles (16 x 76 mm; Beckman 355603) and centrifuged at 1 1 ,000 g (12,700 RPM) in an ultracentrifuge (Beckman, XL100K) for 20 min at 4°C using the pre-cooled 70.1 rotor (Beckman, 342184). Pellets were kept on ice.
  • the solution was then transferred into polycarbonate centrifuge bottles (16 x 76 mm; Beckman 355603) and centrifuged at 15,000 g (14,800 RPM) in an ultracentrifuge (Beckman, XL100K) for 20 min at 4°C using the 70.1 Ti rotor. In the presence of 10% sucrose and at low speed centrifugation, most PHF remained in the supernatant whereas intact or fragmented NFTs and larger PHF aggregates were pelleted. The pellets were discarded. 20% Sarkosyl (Sigma L7414-10ML) was added to the supernatants to a final concentration of 1 % and stirred at room temperature for 1 h.
  • IC50 values of the inhibition of fITau aggregation with Example 44 and Example 46 are indicated in the table below:

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CN113784962A (zh) * 2019-02-27 2021-12-10 加利福尼亚大学董事会 用于治疗脑部疾病的氮杂环庚三烯并-吲哚类和其他杂环
WO2020177952A1 (en) * 2019-03-01 2020-09-10 Ac Immune Sa Novel compounds for the treatment, alleviation or prevention of disorders associated with tau aggregates
CN113453688A (zh) * 2019-03-01 2021-09-28 Ac免疫有限公司 用于治疗、减轻或预防与Tau聚集体相关的病症的新化合物
JP2022521968A (ja) * 2019-03-01 2022-04-13 エイシー イミューン ソシエテ アノニム タウ凝集体に関連する障害の治療、緩和、または予防のための新規化合物
JP7232931B2 (ja) 2019-03-01 2023-03-03 エイシー イミューン ソシエテ アノニム タウ凝集体に関連する障害の治療、緩和、または予防のための新規化合物
WO2021252691A1 (en) * 2020-06-10 2021-12-16 Delix Therapeutics, Inc. Tricyclic psychoplastogens and uses thereof
WO2022232007A1 (en) * 2021-04-25 2022-11-03 University Of Notre Dame Du Lac Modified peptides for the inhibition of abnormal tau accumulation

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